2001 Fiscal Year Final Research Report Summary
Molecular pathogenesis of paroxysmal nocturnal hemoglobinuria as a preleukemia
| Project/Area Number |
12670998
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Hematology
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| Research Institution | Kumamoto University |
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Principal Investigator |
NAKAKUMA Hideki Kumamoto Univ., Sch. of Med., Associate professor, 医学部, 助教授 (90207746)
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| Co-Investigator(Kenkyū-buntansha) |
HORIKAWA Kentaro Kumamoto Univ., Sch. of Med., Instructor, 医学部, 助手 (40322309)
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| Project Period (FY) |
2000 – 2001
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| Keywords | PNH / mutations / T cells / bone marrow cells / HPRT |
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| Research Abstract |
The PIG-A gene mutations result in the hemolysis characteristic of paroxysmal nocturnal hemoglobinuria (PNH). Although the etiology is unclear, mutable conditions have been suggested by the coexistence of multiple clones with different mutations of PIG-A and the occurrence of leukemic clones in PNH patients. To verify this hypothesis, we examined the frequency of hypoxanthine-guanine phosphoribosyl transferase (HPRT) gene mutations that are proven by both resistance to 6-thioguanine (TG) and gene analysis. T cell colonies resistant to 6-TG formed in methylcellulose culture were found in 8 (67%) of 12 PNH patients and 3(18%) of 17 age-matched healthy volunteers (p<0.02, Fisher's probability test). The incidence of resistant colonies ranged from 40 to 367 (mean 149, x10^<-7>) in the 8 patients and from 1 to 16 (mean 7, x10^<-7>) in the 3 healthy donors. Thus, the HRPT gene mutated more frequently in patients with PNH than in healthy controls (p<0.02, Mann-Whitney test). Analysis of bone marrow cells supported these findings. Similar to the PIG-A mutations in PNH, the HPRT mutations were widely distributed in the coding regions and consisted primarily of base deletions. Unlike PNH cells, 6-TG resistant cells expressed CD59, indicating that the HPRT mutations did not occur in PNH clones. No correlation was noted between HPRT mutation frequency and content of therapy received by the patients. In PNG patients, conditions exist that favor the occurrence of diverse somatic mutations in blood cells. The characterization of PNH as a preleukemia would be of help to understand the molecular leukemogenesis.
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Research Products
(2 results)
